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A recent longitudinal population-based study of older women by Mielke et al. showed that high serum ceramide levels were associated with an increased risk of all-cause dementia independent of age, blood glucose, and BMI. These findings are consistent with results of previous postmortem brain studies where total ceramide content has been found to be increased even in cases with mild cognitive decline, and the ceramide mass increase has been attributed to longer acyl chain ceramide species (1). These findings are also supported by the gene expression changes within the canonical sphingolipid metabolism pathway during the earliest recognizable stages of AD (2).

Given the strong evidence of interactions between glucosphingolipids and amyloid-β, their regulation of amyloid-β production, and their role in the cellular survival pathways, it is not surprising to see early changes in ceramide levels during the progression of AD. That the current study identified these alterations in blood is compelling, and points to the potential role of cardiovascular risk factors in dementia and its progression. A majority of epidemiologic studies support a role for cardiovascular disease and cerebral ischemia as risk factors for AD. Microvascular dysfunction is a prominent underlying cause of silent strokes that are not in themselves symptomatically recognized, but may cumulatively represent a major contributor to cognitive impairment in elderly persons (3). It would be interesting to see which cardiovascular risk factors influence the production of ceramide in the periphery, and whether available treatments for cardiovascular disease affect the associations between serum ceramide and dementia. The current findings also have a potential for the development of convenient and accurate peripheral biomarkers of prodromal AD.